title: Progranulin protects vascular endothelium against atherosclerotic inflammatory reaction via Akt/eNOS and nuclear factor-κB pathways.
abstract: OBJECTIVE
  Atherosclerosis is considered a chronic inflammatory disease, initiated by activation and dysfunction of the endothelium. Recently, progranulin has been regarded as an important modulator of inflammatory processes; however, the role for prgranulin in regulating inflammation in vascular endothelial cells has not been described.
  
  
  RESULTS
  Signaling pathways mediated by progranulin were analyzed in human umbilical vein endothelial cells (HUVECs) treated with progranulin. Progranulin significantly induced Akt and endothelial nitric oxide synthase (eNOS) phosphorylation in HUVECs, an effect that was blocked with Akt inhibitor. Furthermore, nitric oxide (NO) level, the end product of Akt/eNOS pathway, was significantly upregulated after progranulin treatment. Next, we showed that progranulin efficiently inhibited lipopolysaccharide (LPS)-mediated pro-inflammatory signaling. LPS-induced phosphorylation of IκB and nuclear factor-κB (NF-κB) levels decreased after progranulin treatment. Also, progranulin blocked translocation of NF-κB from the cytosol to the nucleus. In addition, progranulin significantly reduced the expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) by inhibiting binding of NF- κB to their promoter regions and blocked attachment of monocytes to HUVECs. Progranulin also significantly reduced the expression of tumor necrosis factor receptor-α (TNF-α) and monocyte chemo-attractant protein-1 (MCP-1), the crucial inflammatory molecules known to aggravate atherosclerosis.
  
  
  CONCLUSIONS
  Progranulin efficiently inhibited LPS-mediated pro-inflammatory signaling in endothelial cells through activation of the Akt/eNOS pathway and attenuation of the NF-κB pathway, suggesting its protective roles in vascular endothelium against inflammatory reaction underlying atherosclerosis.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea.
authors.forename: Hwan-Jin
authors.initials: HJ
authors.lastname: Hwang
authors.forename: Tae Woo
authors.initials: TW
authors.lastname: Jung
authors.forename: Ho Cheol
authors.initials: HC
authors.lastname: Hong
authors.forename: Hae Yoon
authors.initials: HY
authors.lastname: Choi
authors.forename: Ji-A
authors.initials: JA
authors.lastname: Seo
authors.forename: Sin Gon
authors.initials: SG
authors.lastname: Kim
authors.forename: Nan Hee
authors.initials: NH
authors.lastname: Kim
authors.forename: Kyung Mook
authors.initials: KM
authors.lastname: Choi
authors.forename: Dong Seop
authors.initials: DS
authors.lastname: Choi
authors.forename: Sei Hyun
authors.initials: SH
authors.lastname: Baik
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Yoo
mesh_terms: D050197:Atherosclerosis / Q000503:physiopathology*; D015153:Blotting, Western; D018932:Chemokine CCL2 / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D016328:NF-kappa B / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D000077153:Progranulins; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D017931:DNA Primers; C492314:GRN protein, human; D018836:Inflammation Mediators; D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B; D000077153:Progranulins; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt